Bacterial resistance to antibiotics is a widespread problem with grave implications for public health. Most bacteria have a genome that consists of a single chromosome and, consequently, replicate using a process that is simpler than mitosis or meiosis. Because bacteria can grow and divide at a rate that is much faster than that of eukaryotic cells, they can undergo evolution, i.e., natural selection, to produce a significant number of multidrug-resistant strains on a time scale that is short enough to pose a serious threat to human health worldwide. Much of the rise in multidrug-resistant bacterial strains can be attributed to the overuse and misuse of antibiotics, by patients and physicians alike. Multidrug-resistant bacterial strains may also be engineered by persons with nefarious goals, e.g., bioterrorists. Therefore, the development of new antibiotics must be an ongoing endeavor.
Bacillus anthracis (BA) and Staphylococcus aureus (SA) are important human pathogens, but for very different reasons. BA is the causative agent of anthrax, which is a serious and fatal disease, and is considered an agent of biological warfare or terrorism.1,2 Although it holds great potential as a biological weapon of mass destruction (WMD), the intentional use of this organism to infect our population has, to date, been limited to the letter attacks in 2001. While efforts to develop better-defined vaccines to the prophylaxis of anthrax are actively ongoing, their use for administration to humans is limited and their availability is very restricted.3 Although doxycycline and ciprofloxacin can be used to treat anthrax upon immediate administration to infected patients,4,5 BA resistance to ciprofloxacin, doxycycline and macrolides have appeared in the literature.6-8 Furthermore, capable terrorists can engineer the resistance to these antibiotics.
In contrast to BA, SA is one of the most common causes of infection in the U.S., attributable in large part to its propensity to become multidrug-resistant.9,10 The Infectious Disease Society of America has classified it as one of the “ESKAPE’ pathogens that can readily develop resistance to the biocidal action of antibiotics.11,12 Currently, vancomycin is the most common first-line treatment for antibiotic-resistant SA infections.13 However, its overutilization has resulted in an increase in vancomycin-resistant Staphylococcus aureus strains.9,14-16 Further, except for the addition of the oxazolidinone linezolid17 in 2000, the lipopeptide daptomycin18 in 2003, and the FDA's recent approval of ceftaroline,19 tedizolid,20 and dalbavancin,21 the options to treat infections caused by SA are limited. Additionally, although these recently approved and late-stage antibiotics in development may prove invaluable in combating SA resistance, these bacteria will almost inevitably develop resistance to new antibacterial agents introduced to the clinic.22 For instance, reports of resistance to linezolid and daptomycin have quickly emerged upon their introduction. In essence, antibiotic resistance is occurring faster than new compounds can be introduced into clinical practice.
Compounding this problem is the propensity of SA to form biofilms, which are a leading cause of chronic infections in medical devices and are tolerant to most currently available antibiotics. Biofilm-growing bacteria are known to mutate at a higher frequency compared to planktonic, isogenic bacteria, and thus can more quickly undergo natural selection and gain resistance to antibiotics. Additionally, biofilms thrive under hypoxic conditions, which retards growth, metabolic activity, and protein synthesis. Thus, when bacteria are producing biofilms, they are said to be in a non-replicative, “stationary” phase. Most drugs are ineffective against bacteria in such a phase, even when their planktonic progenitors remain susceptible to the same drugs. To date, no antibiofilm agents have been made available for clinical use. Thus, there is a need for new drug for combating biofilm-related infections.